Influenza A H1N1–mediated pre-existing immunity to SARS-CoV-2 predicts COVID-19 outbreak dynamics

  1. Nerea Martín Almazán
  2. Afsar Rahbar
  3. Marcus Carlsson
  4. Tove Hoffman
  5. Linda Kolstad
  6. Bengt Rönnberg
  7. Mattia Russel Pantalone
  8. Ilona Lewensohn Fuchs
  9. Anna Nauclér
  10. Mats Ohlin
  11. Mariusz Sacharczuk
  12. Piotr Religa
  13. Stefan Amér
  14. Christian Molnár
  15. Åke Lundkvist
  16. Andres Susrud
  17. Birger Sörensen
  18. Cecilia Söderberg-Nauclér

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Abstract

Background

Susceptibility to SARS-CoV-2 infections is highly variable, ranging from asymptomatic and mild infections in most, to deadly outcome in few. This individual difference in susceptibility and outcome could be mediated by a cross protective pre-immunity, but the nature of this pre-immunity has remained elusive.

Methods

Antibody epitope sequence similarities and cross-reactive T cell peptides were searched for between SARS-CoV-2 and other pathogens. We established an ELISA test, a Luminex Multiplex bead array assay and a T cell assay to test for presence of identified peptide specific immunity in blood from SARS-CoV-2 positive and negative individuals. Mathematical modelling tested if SARS-CoV-2 outbreak dynamics could be predicted.

Findings

We found that peptide specific antibodies induced by influenza A H1N1 (flu) strains cross react with the most critical receptor binding motif of the SARS-CoV-2 spike protein that interacts with the ACE2 receptor. About 55–73% of COVID-19 negative blood donors in Stockholm had detectable antibodies to this peptide, NGVEGF, in the early pre-vaccination phase of the pandemic, and seasonal flu vaccination trended to enhance SARS-CoV-2 antibody and T cell immunity to this peptide. Twelve identified flu/SARS-CoV-2 cross-reactive T cell peptides could mediate protection against SARS-CoV-2 in 40–71% of individuals, depending on their HLA type. Mathematical modelling taking pre-immunity into account could fully predict pre-omicron SARS-CoV-2 outbreaks.

Interpretation

The presence of a specific cross-immunity between Influenza A H1N1 strains and SARS-CoV-2 provides mechanistic explanations to the epidemiological observations that influenza vaccination protects people against SARS-CoV-2 infection.

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  1. Version published to 10.1101/2021.12.23.21268321v2 on medRxiv
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    SciScore for 10.1101/2021.12.23.21268321: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Ethicsnot detected.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    No key resources detected.

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a protocol registration statement.

    Results from scite Reference Check: We found no unreliable references.

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  3. Version published to 10.1101/2021.12.23.21268321v1 on medRxiv